The long term goal of the present proposal is to continue an analysis of drug actions on regional myocardial blood flow and cardiac muscle function in different models of ischemia. One major objective will be to determine mechanisms whereby specific pharmacological agents influence the distribution of coronary blood flow across the left ventricular wall in the normal coronary circulation and in the coronary circulation with various degrees of coronary artery stensosis or total coronary artery occlusion. Dogs with immature or poorly developed collaterals (acute coronary occlusion) and those with mature or well developed collateral vessels (chronic occlusion ) will be utilized. Myocardial segment function (ultrasonic crystals) will be monitored in normal and ischemic zones and changes in segment shortening will be correlated with changes in regional myocardial blood flow (radioactive microspheres). By using these techniques in anesthetized dogs, the proposed research will determine the in vivo significance of endothelium-derived relaxing factor (EDRF) as an important endogenous mediator of the left ventricular transmural distribution of coronary blood flow. A systematic evaluation of the effects of endothelium-dependent (acetylcholine, arachidonic acid, bradykinin) vs. -independent (sodium nitroprusside, glyceryl trinitrate) vasodilators on myocardial blood flow in the normal and ischemic coronary circulation will be undertaken. Experiments will be completed testing the hypothesis that endothelium-dependent vasodilators are directly (without alterations in systemic hemodynamics) capable of redistributing coronary blood flow preferentially to the subendocardium, an area susceptible to ischemic insult. Other experiments will be completed demonstrating the influence of pharmacological blockade of production, inhibition of release or inactivation of EDRF on the actions of endothelium-dependent vs. - independent vasodilators. Physical damage of vascular endothelium in the coronary circulation will be accomplished by several procedures and verified by electron microscopy. Little information has been obtained regarding the in vivo significance of EDRF. The experiments proposed will help to define the importance of EDRF in the normal coronary circulation and in models of coronary artery disease. These studies should lend important insight as to mechanisms by which certain pharmacological agents relieve myocardial ischemia in patients with coronary artery disease.